The present invention relates to new thienylazolylalkoxyethanamines of general formula (I), as well as their physiologically acceptable salts, to the procedures for their preparation, to their application as medicaments in human and/or veterinary therapy and to the pharmaceutical compositions that contain them. 
The new compounds object of the present invention can be used in the pharmaceutical industry as intermediates and for the preparation of medicaments.
The invention also relates to new derivatives of thienylazolylcarbinols, of general formula (IV), useful as starting materials or intermediates in the synthesis of the compounds of general formula (I).
In our patent application EP 289380 we have described different derivatives of phenylpyrazolylcarbinols, of general formula (II) 
in which R1 represents a hydrogen atom or an alkyl group; R2 represents an aminoalkyl radical and Het represents an azol.
We have now discovered that substituting a benzene ring for a thiopheno ring gives rise to new compounds of general formula (I) that show some interesting biological properties. These properties make the new compounds particularly useful for use in human and/or veterinary therapy. The compounds object of this patent are useful as agents with analgesic activity.
The present invention provides new compounds with potent analgesic activity.
The compounds object of the present invention correspond to the general formula (I) 
in which
R1 represents a hydrogen atom, a halogen atom or a lower alkyl radical; R2, R3 and R4 represent a hydrogen atom or a lower alkyl radical; and Az represents an nitrogenated heterocyclic aromatic five-member ring, N-methyl substituted, that contains from one to three atoms of nitrogen, of general formula (III) 
in which Z1, Z2 and Z3, independently, represent an atom of nitrogen or CH. with the condition that, at least, one of Z1, Z2 or Z3 is CH.
The term xe2x80x9clower alkylxe2x80x9d represents a linear or branched carbon chain that includes from 1 to 4 atoms of carbon, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and terc-butyl for example.
The new compounds of general formula (I) have at least one asymmetric carbon and so can be prepared enantiomerically pure or as racemates. The racemates of the compounds (I) can be resolved into their optical isomers by conventional methods, such as for example separation by chiral chromatography or fractionated crystallisation of their diastereoisomeric salts, which can be prepared by reaction of the compounds (I) with enantiomerically pure acids. Similarly, they can also be obtained by enantioselective synthesis using chiral precursors, preferably enantiomerically pure thienylazolylcarbinols.
The present invention relates equally to the physiologically acceptable salts of the compounds of general formula (I), in particular the addition salts of mineral acids such as hydrochloric, hydrobromic, phosphoric, sulphuric, nitric acids and organic acids such as citric, malic, fumaric, tartaric or its derivatives, p-toluensulphonic, methanesulphonic, canphosulfonic, etc., acids.
In an embodiment, the invention provides a compound of formula (I) wherein R1 is a halogen atom wherein said halogen atom represents a fluorine, chlorine, or bromine atom.
In a particular embodiment, the invention provides a compound of formula (I) selected from the following group:
[1] 5-{xcex1-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol;
[2] Citrate of 5-{xcex1-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol;
[3] 5-{xcex1-[2-(dimethylamino)ethoxy]-3-thienylmethyl}-1-methyl-1H-pyrazol;
[4] 2-{xcex1-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-imidazol;
[5] 5-{xcex1-[2-(dimethylamino)ethoxy]-3-methyl-2-thienylmethyl}-1-methyl-1H-pyrazol;
[6] 5-{xcex1-[2-(dimethylamino)ethoxy]-5-methyl-2-thienylmethyl}-1-methyl-1H-pyrazol;
[7] 5-{xcex1-[2-(dimethylamino)ethoxy]-5-bromo-2-thienylmethyl}-1-methyl-1H-pyrazol;
[8] 5-{xcex1-[2-(dimethylamino)ethoxy]-4-bromo-2-thienylmethyl}-1-methyl-1H-pyrazol;
[9] 5-{1-[2-(dimethylamino)ethoxy]-1-(2-thienyl)ethyl}-1-methyl-1H-pyrazol;
[10] (+)-5-{xcex1-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol;
[11] (xe2x88x92)-5-{xcex1-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol;
[12] Citrate of (+)-5-{xcex1-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol;
[13] Citrate of (xe2x88x92)-5-{xcex1-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol;
[14] D-toluoyltartrate of (+)-5-{xcex1-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol; and
[15] D-toluoyltartrate of (xe2x88x92)-5-{xcex1-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol.
The new derivatives of general formula (I), in which R1, R2, R3, R4 and Az have the aforementioned meaning, can be prepared according to the methods that are now described:
Method A
By reaction of a compound of general formula IV 
with a compound of general formula V 
in which R1 to R4 and Az have the aforementioned meaning and X represents a halogen atom, preferably chlorine, or a leaving group such as tosiloxy or mesiloxy.
The reaction of the compound of general formula IV with a compound of general formula V in the form a base or salt, is carried out in the presence of an appropriate solvent such as a hydrocarbon such as benzene or toluene for example or in halogenated solvents such as chloromethane or tetrachloromethane or in ethers such as tetrahydrofurane or in aprotic dipolar solvents such as dimethylsulphoxide or dimethylformamide.
The reaction is preferably carried out in the presence of an appropriate base such as the mineral bases such as sodium hydroxide or potassium hydroxide or the carbonates or bicarbonates of sodium or potassium for example.
The reaction is preferably carried out in the presence of a phase transfer catalyst such as tetrabutylamonium bromide, triethylbenzylamonium chloride or crown ethers, in a temperature range lying between room temperature and the solvent reflux temperature.
Method B
By reaction of a compound of general formula VI 
with a compound of general formula VII 
in which R1 to R4 and Az have the aforementioned meaning and Y represents a halogen atom, preferably chlorine, a leaving group such as tosiloxy or mesiloxy or a hydroxyl radical.
The reaction of the compound of general formula VI with a compound of general formula VII in the form a base or salt, is carried out in the presence of an appropriate solvent such as a hydrocarbon such as benzene or toluene for example or in halogenated solvents such as chloromethane or tetrachloromethane or in ethers such as tetrahydrofurane or in aprotic dipolar solvents such as dimethylsulphoxide or dimethylformamide.
The reaction is preferably carried out in the presence of an appropriate base such as the mineral bases such as sodium hydroxide or potassium hydroxide or the carbonates or bicarbonates of sodium or potassium for example.
The reaction can be carried out in the presence of a phase transfer catalyst such as tetrabutylamonium bromide, triethylbenzylamonium chloride or the crown ethers, in a temperature range lying between room temperature and the solvent reflux temperature.
When Y represents a hydroxyl radical the reaction is preferably carried out in the presence of a strong acid such as sulphuric acid, in or not in the presence of an appropriate solvent such as benzene and in a temperature range lying between room temperature and the reflux temperature of the solvent.
Method C
By reduction of a compound of general formula VIII 
in which R1 and Az have the aforementioned meaning,
whereupon an intermediate compound is obtained of general formula IV in which R1 and Az have the aforementioned meaning and R2 represents a hydrogen atom.
The reduction is carried out with hydrides such as aluminium hydride and lithium hydride in an appropriate solvent such as for example an ether such as tetrahydrofurane, dimethylether or dioxane, or else with boron hydride and sodium in an alcohol such as methanol or ethanol, or else with hydrogen in an appropriate solvent such as an alcohol, hydrocarbon or ether with an appropriate catalyst such as Raney nickel, platinum oxide or palladium. In the case of hydrogenation the pressure of hydrogen preferably lies between 1.01 and 20.2 bars (1 and 20 atmospheres), the temperatures vary between 20 and 100xc2x0 C. and the reaction time between 1 and 24 hours.
Method D
By addition of organometallic compounds to carbonyl compounds, for example, by the reaction of a carbonyl compound of general formula IX 
with organometallic reagents of general formula Az-M (Method D-1) or else (Method D-2), by reaction of a carbonyl compound of general formula X 
with organometallic reagents of general formula XI 
in which R1, R2 and Az have the aforementioned meaning and M represents an atom of lithium or the MgX function of the Grignard reagents, where X represents a halogen, preferably a bromine atom, whereupon an intermediate compound is obtained of general formula IV in which R1, R2 and Az have the aforementioned meaning.
Method E
The salts of the compounds of general formula (I) are prepared by the reaction of a compound of general formula (I) with an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, nitric acid or with organic acids such as citric, malic, fumaric, tartaric or its derivatives, p-toluensulphonic, methansulphonic, etc., acid, in an appropriate solvent such as methanol, ethanol, ethyl ether, ethyl acetate, acetonitrile or acetone, obtaining the corresponding salts with the usual techniques of precipitation or crystallisation.
Method F
The preparation of the compounds of general formula (I) in enantiomerically pure form in accord with the present invention is based on the optical resolution of a racemic amine by the employment of an optically active acid in which at least one of the enantiomers is capable of forming a diastereoisomeric salt between an enantiomer of the compound of general formula (I) and an enantiomer of a chiral acid, such as tartaric acid and its dibenzoyltartaric, ditoluyltartaric, and other derivatives, malic acid, mandelic acid and their derivatives, canphorsulphonic acid and its derivatives, among others. The chiral acid employed can be used either on its own or forming part of a mixtures with other inorganic and organic acids, either chiral or non-chiral, such as hydrochloric acid, p-toluensulphonic, methansulphonic acid, in molar ratios that range from 0.5% to 50%. Preferably, the chiral acid is selected from (xe2x88x92)-ditoluoyl-L-tartaric acid and (+)-ditoluoyl-D-tartaric acid, either on their own or else mixed, individually, with p-toluensulphonic acid.
The procedure is carried out in an appropriate solvent such as water, acetone, acetonitrile, methanol, ethanol, isopropanol, ter-butanol, dichloromethane, chloroform, carbon tetrachloride, dimethylformamide, dimethylsulphoxide, ethyl acetate, tetrahydrofurane, 1,4-dioxane, ethylenglycol, 1,2-dimethoxyethane, and in general any solvent susceptible to being used in a chemical process. The procedure can be carried out in a temperature range lying between xe2x88x9220xc2x0 C. and the reflux temperature of the reaction mixture. The diastereoisomeric salt, once formed, can be separated by conventional methods such as fractionated crystallisation, chromatography and other methods. This resolution procedure can be used to resolve racemic mixtures of a compound of general formula (I) (that is to say, those mixtures in which the two enantiomers are found in a 1:1 ratio) or to resolve non-racemic mixtures of a compound of general formula (I) (mixtures in which one of the enantiomers is the major component), obtained by any physical or chemical method.
The invention provides pharmaceutical compositions that comprise, as well as an acceptable pharmaceutical excipient, at least one compound of general formula (I) or one of their physiologically acceptable salts. The invention also relates to the use of a compound of general formula (I) and its physiologically acceptable salts in the manufacture of a medicament with analgesic activity.
The invention also relates to new derivatives of thienylazolylcarbinols, of general formula (IV) 
in which
R1 is a hydrogen or halogen atom, or an alkyl radical of 1 to 4 carbon atoms;
R2 is an atom of hydrogen or an alkyl radical of 1 to 4 carbon atoms; and
Az is N-methylpyrazol.
Compounds of formula (IV) are useful as starting materials or intermediates in the synthesis of the compounds of general formula (I).
In a particular embodiment, the invention provides a compound of formula (IV) selected from the following group:
[16] 5-(xcex1-hydroxy-2-thienylmethyl)-1-methyl-1H-pyrazol;
[17] 5-(xcex1-hydroxy-3-methyl-2-thienylmethyl)-1-methyl-1H-pyrazol;
[18] 5-(xcex1-hydroxy-5-methyl-2-thienylmethyl)-1-methyl-1H-pyrazol;
[19] 5-(xcex1-hydroxy-5-bromo-2-thienylmethyl)-1-methyl-1H-pyrazol;
[20] 5-(xcex1-hydroxy-4-bromo-2-thienylmethyl)-1-methyl-1H-pyrazol; and
[21] 5-[1-hydroxy-1-(2-thienyl)ethyl]-1-methyl-1H-pyrazol.